Triclosan and silver compound containing medical devices

ABSTRACT

The present invention relates to polymeric medical articles comprising combinations of triclosan and silver-containing compounds. It is based, at least in part, on the discovery that these agents act synergistically, thereby permitting the use of relatively low levels of both agents. While it had been previously found that triclosan can be particularly useful when used in conjunction with chlorhexidine, it has been further discovered that medical articles having suitable antimicrobial properties may be prepared, according to the present invention, which contain triclosan without chlorhexidine. Such medical articles offer the advantage of preventing or inhibiting infection while avoiding undesirable adverse reactions to chlorhexidine by individuals that may have sensitivity to chlorhexidine.

This is a continuation of application ser. No. 09/281,872, filed Mar.31, 1999 now U.S. Pat. No. 6,224,579.

1.0 INTRODUCTION

The present invention relates to medical devices comprising synergisticcombinations of triclosan and silver containing compounds.

2.0 BACKGROUND OF THE INVENTION

Whenever a medical device comes in contact with a patient, a risk ofinfection is created. Thus, a contaminated examination glove, tonguedepressor, or stethoscope could transmit infection. The risk ofinfection dramatically increases for invasive medical devices, such asintravenous catheters, arterial grafts, intrathecal or intracerebralshunts and prosthetic devices, which not only are, themselves, inintimate contact with body tissues and fluids, but also create a portalof entry for pathogens.

A number of methods for reducing the risk of infection have beendeveloped which incorporate anti-infective agents into medical devices,none of which have been clinically proven to be completely satisfactory.Such devices desirably provide effective levels of anti-infective agentduring the entire period that the device is being used. This sustainedrelease may be problematic to achieve, in that a mechanism fordispersing anti-infective agent over a prolonged period of time may berequired, and the incorporation of sufficient amounts of anti-infectiveagent may adversely affect the surface characteristics of the device.The difficulties encountered in providing effective antimicrobialprotection increase with the development of drug-resistant pathogens.

One potential solution to these problems is the use of a synergisticcombination of anti-infective agents that requires relatively lowconcentrations of individual anti-infective agents which may havediffering patterns of bioavailability.

Two well-known anti-infective agents are chlorhexidine and triclosan.The following patents and patent application relate to the use ofchlorhexidine and/or triclosan in medical devices.

U.S. Pat. No. 4,723,950 by Lee relates to a microbicidal tube which maybe incorporated into the outlet tube of a urine drainage bag. Themicrobicidal tube is manufactured from polymeric materials capable ofabsorbing and releasing anti-microbial substances in a controllablesustained time release mechanism, activated upon contact with dropletsof urine, thereby preventing the retrograde migration of infectiousorganisms into the drainage bag. The microbicidal tube may be producedby one of three processes: (1) a porous material, such as polypropylene,is impregnated with at least one microbicidal agent, and then coatedwith a hydrophilic polymer which swells upon contact with urine, causingthe leaching out of the microbicidal agent; (2) a porous material, suchas high density polyethylene, is impregnated with a hydrophilic polymerand at least one microbicidal agent; and (3) a polymer, such assilicone, is compounded and co-extruded with at least one microbicidalagent, and then coated with a hydrophilic polymer. A broad range ofmicrobicidal agents are disclosed, including chlorhexidine andtriclosan, and combinations thereof. The purpose of Lee's device is toallow the leaching out of microbicidal agents into urine contained inthe drainage bag; similar leaching of microbicidal agents into thebloodstream of a patient may be undesirable.

U.S. Pat. No. 5,091,442 by Milner relates to tubular articles, such ascondoms and catheters, which are rendered antimicrobially effective bythe incorporation of a non-ionic sparingly soluble antimicrobial agent,such as triclosan. The tubular articles are made of materials whichinclude natural rubber, polyvinyl chloride and polyurethane.Antimicrobial agent may be distributed throughout the article, or in acoating thereon. A condom prepared from natural rubber latex containing1% by weight of triclosan, then dipped in an aqueous solution ofchlorhexidine, is disclosed. U.S. Pat. Nos. 5,180,605 and 5,261,421,both by Milner, relate to similar technology applied to gloves.

U.S. Pat. Nos. 5,033,488 and 5,209,251, both by Curtis et al., relate todental floss prepared from expanded polytetrafluoroethylene (PTFE) andcoated with microcrystalline wax. Antimicrobial agents such aschlorhexidine or triclosan may be incorporated into the coated floss.

U.S. Pat. No. 5,200,194 by Edgren et al. relates to an oral osmoticdevice comprising a thin semipermeable membrane wall surrounding acompartment housing a “beneficial agent” (that is at least somewhatsoluble in saliva) and a fibrous support material composed ofhydrophilic water-insoluble fibers. The patent lists a wide variety of“beneficial agents” which may be incorporated into the oral osmoticdevice, including chlorhexidine and triclosan.

U.S. Pat. No. 5,019,096 by Fox, Jr., et al. relates toinfection-resistant medical devices comprising a synergistic combinationof a silver compound (such as silver sulfadiazine) and chlorhexidine.

International Patent Application No. PCT/GB92/01481, Publication No. WO93/02717, relates to an adhesive product comprising residues of acopolymerisable emulsifier comprising a medicament, which may bepovidone iodine, triclosan, or chlorhexidine.

International Patent Application No. PCT/US96/20932, Publication No. WO97/25085, relates to polymeric medical articles comprising synergisticcombinations of chlorhexidine and triclosan which utilize relatively lowlevels of these agents.

In contrast to the present invention, none of the above-cited referencesteach medical articles comprising synergistic combinations of triclosanand silver compounds which utilize relatively low levels of these agentsand provide effective levels of antimicrobial activity, even in theabsence of chlorhexidine.

3.0 SUMMARY OF THE INVENTION

The present invention relates to polymeric medical articles comprisingcombinations of triclosan and/or other chlorinated phenols andsilver-containing compounds. It is based, at least in part, on thediscovery that these agents act synergistically, thereby permitting theuse of relatively low levels of both agents. While it had beenpreviously found that triclosan can be particularly useful when used inconjunction with chlorhexidine, it has been further discovered thatmedical articles having suitable antimicrobial properties may beprepared, according to the present invention, which contain triclosanand a silver compound without chlorhexidine. Such medical articles offerthe advantage of preventing or inhibiting infection while avoidingundesirable adverse reactions to chlorhexidine by individuals that mayhave a sensitivity to chlorhexidine, such as a chlorhexidine allergy.

The present invention is also based, at least in part, on the discoverythat the surface of medical articles, especially catheters, impregnatedwith triclosan and silver compounds generally were found to be smootherand shinier in comparison with catheters impregnated with triclosan andchlorhexidine. Even when the triclosan-silver compound impregnatedcatheters exhibited commensurate or smaller zones of inhibition comparedto triclosan-chlorhexidine catheters, there was little or no bacterialadherence observed on the former when exposed to bacterial culture.Microbial adherence on the surfaces of medical devices are the result ofa deposition of fibrinogen and fibronectin on the surface which forms ahost biofilm. Because bacteria tend to adhere to this biofilm,glycocalyx forms which serves as a bacterial reservoir causing bloodstream infections. Without being bound by any particular theory, it isbelieved that medical articles of the invention, by virtue of theirsmooth surfaces, may be less physically irritating than prior artdevices, may be less likely to provoke fibrinogen and/or fibronectindeposition, and therefore may avoid bacterial colonization.

4.0 DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to medical articles comprisingcombinations of triclosan and/or another chlorinated phenol and one ormore silver-containing compound (hereafter, “silver compound”).

While not being bound or limited by any particular theory, it isbelieved that the combination of triclosan and a silver compound forms asoluble complex. This would explain observations, such as those setforth in Example Section 5 below, that the presence of triclosanimproves the solubility of various silver compounds, thereby improvingtheir bioavailability.

As shown in Example Sections 7, 9-17 and 19, medical articles, which maybe hydrophilic or hydrophobic, treated with combinations of triclosanand various silver compounds exhibit desirable antimicrobial properties.As shown in Example Sections 8, 13 and 14 such articles exhibit smoothsurfaces that tend to resist bacterial adherence, which may be at leastpartly responsible for their antimicrobial quality.

The present invention provides for medical articles treated withchlorinated phenols other than triclosan in combination with one or moresilver compound. As shown in Example Section 18, such combinationsresult in enhanced antimicrobial activity. Suitable chlorinated phenolsinclude parachlorometaxylenol (“PCMX”) and dichlorometaxylenol (“DCMX”).The amount of chlorinated phenol which may be used is as set forth belowfor triclosan, but may be adjusted for differences in potency whentested against a particular microbe. For example, in specific,non-limiting embodiments of the invention polymeric medical articles maybe prepared using treatment solutions comprising between about 0.1 and 5percent, preferably between about 0.3 and 1.5 percent, of a silvercompound, and between about 0.1 and 20 percent, preferably between about0.1 and 8 percent, of a chlorinated phenol, preferably PCMX. The presentinvention also provides for medical articles comprising triclosan inaddition to another chlorinated phenol.

In additional embodiments, the present invention provides for medicalarticles having anti-infective activity which comprise triclosan and/oranother chlorinated phenol, a silver compound, and an anti-inflammatoryagent. It has been found that the addition of an anti-inflammatorycompound enhances the antimicrobial activity of such devices (seeSection 17 below).

In still further embodiments, the present invention provides for medicalarticles which have been treated with a hydrogel, and further comprise ametal compound.

The term triclosan (“TC”), as used herein, refers to a compound alsoknown as 2,4,4′-trichloro-2′-hydroxydiphenyl ether and also known as5-chloro-2-(2,4-dichlorophenoxy)phenol

The term silver compound, as used herein, refers to a compoundcomprising silver, either in the form of a silver atom or a silver ionunlinked or linked to another molecule via a covalent or noncovalent(e.g., ionic) linkage, including but not limited to covalent compoundssuch as silver sulfadiazine (“AgSD”) and silver salts such as silveroxide (“Ag₂O”), silver carbonate (“Ag₂CO₃”), silver deoxycholate, silversalicylate, silver iodide, silver nitrate (“AgNO₃”), silverparaaminobenzoate, silver paraaminosalicylate, silver acetylsalicylate,silver ethylenediaminetetraacetic acid (“Ag EDTA”), silver picrate,silver protein, silver citrate, silver lactate and silver laurate.

The terms “medical article” and “medical device” are usedinterchangeably herein. Medical articles that may be treated accordingto the invention are either fabricated from or coated or treated withbiomedical polymer (and hence may be referred to as “polymer-containingmedical articles”) and include, but are not limited to, cathetersincluding urinary catheters and vascular catheters (e.g., peripheral andcentral vascular catheters), wound drainage tubes, arterial grafts, softtissue patches (such as polytetrafluoroethylene (“PTFE”) soft tissuepatches), gloves, shunts, stents, tracheal catheters, wound dressings,sutures, guide wires and prosthetic devices (e.g., heart valves andLVADs). Vascular catheters which may be prepared according to thepresent invention include, but are not limited to, single and multiplelumen central venous catheters, peripherally inserted central venouscatheters, emergency infusion catheters, percutaneous sheath introducersystems and thermodilution catheters, including the hubs and ports ofsuch vascular catheters. The present invention may be further applied tomedical articles that have been prepared according to U.S. Pat. No.5,019,096 by Fox, Jr. et al.

The following are descriptions of particular embodiments of theinvention.

Percentages recited herein refer to weight/volume (w/v), except asindicated otherwise.

The present invention provides, in various non-limiting embodiments,for: (1) treatment solutions comprising between about 0.1 and 5 percent,and preferably between about 0.3 and 1.5 percent of a silver compound;and between about 0.1 and 20 percent and preferably between about 0.1and 8 percent of triclosan and/or other chlorinated phenol; (2)treatment solutions comprising between about 0.1 and 10 percent, andpreferably between about 1 and 5 percent of one or more hydrophilic orhydrophobic polymer; between about 0.1 and 5 percent, and preferablybetween about 0.3 and 1.5 percent of a silver compound; and betweenabout 0.1 and 20 percent, and preferably between about 0.1 and 8 percentof triclosan and/or other chlorinated phenol; (3) polymer-containingmedical articles treated with a treatment solution as set forth in (1)or (2) above, and articles physically equivalent thereto (that is tosay, articles prepared by a different method but having essentially thesame elements in the same proportions); (4) polymer-containing medicalarticles treated with treatment solutions set forth in (1) or (2) abovewherein the articles are dried and thereafter coated with ananti-infective and/or polymeric coating in accordance with a two-stepprocess. The treatment solutions set forth in (1) or (2) may optionallyfurther comprise (i) an organic acid, at a concentration of betweenabout 0 and 5 percent, preferably between about 0.1 and 2 percent; (ii)an anti-inflammatory agent, at a concentration of between about 1 and 5percent, preferably between about 0.1 and 1 percent; (iii) anantimicrobial other than a silver compound or triclosan at aconcentration of between about 0.1 and 10 percent; and/or (iv) ahydrogel at a concentration of between about 0.5 to 10 percent,preferably between about 1 and 5 percent. In preferred non-limitingembodiments of the invention, the amount of silver present as silveratom or silver ion is about 0.9%. In preferred non-limiting embodimentsof the invention, the treatment solution and/or medical article does notcontain chlorhexidine or a chlorhexidine salt. The medical articles are“treated” by exposing them, for an effective period of time, to thetreatment solution, where an “effective period of time” is that periodof time sufficient to introduce anti-infective quantities of triclosanand/or other chlorinated phenol and silver compound. Where theconcentration of gtriclosan and/or other chlorinated phenol in thetreatment solution is between 0.1 and 8 percent, the effective period oftime may be between about 30 seconds and one hour; where theconcentration of tricolsan and/or other chlorinated phenol in thetreatment solution is between about 9 and 20 percent, the effectiveperiod of time may be between about 10 seconds and 2 minutes. Longerperiods of exposure may be used provided that undesirable deteriorationof the medical article does not occur.

The term “about” indicates a variation within 20 percent.

In particular non-limiting embodiments of the invention, where themedical article is a vascular catheter, such as a central venouscatheter, the amount of triclosan contained is about 100-600 μg/cm,preferably about 400-500 μg/cm and the amount of silver atom or ion is25 to 100 μg/cm, preferably 30 to 80 μg/cm. The triclosan and silver arein releasable form, i.e., extractable by a solvent that does notsubstantially dissolve the catheter.

Medical articles prepared according to the invention may be treated ontheir external surface, internal surface, or both. For example, and notby way of limitation, where the medical article is a catheter, theinternal surface and/or external surface of the catheter may be treatedaccording to the invention. For example, where it is desired to treatboth internal and external surfaces, an open-ended catheter may beplaced in a treatment solution such that the treatment solution fillsthe catheter lumen. If only the external surface is to come in contactwith treatment solution, the ends of the catheter may be sealed beforeit is placed in the treatment solution. If only the internal surface isto come in contact with treatment solution, the solution may be allowedto pass through and fill the lumen but the catheter is not immersed inthe treatment solution.

Medical articles may be dipped, soaked, or otherwise have a surfacecoated. The term “dipped” suggests briefer exposure to treatmentsolution relative to soaking, and preferably is for a period of timeless than fifteen minutes.

Successful treatment of a medical article with a polymer comprising ananti-infective agent may be problematic, particularly where the medicalarticle has a hydrophobic surface. The adherence of the polymer maydepend upon (1) the polymeric matrix in which the anti-infective agentis suspended; (2) compatibility (or lack thereof) between theagent-polymeric matrix and the surface of the article; (3) the solventsystem; and (4) the thickness of polymer/anti-infective agent desirablyapplied. Furthermore, the rates of release of various anti-infectiveagents from diverse polymers may differ. To address these issues, thepresent invention provides for two different methods for treatingmedical articles: a one-step method, and a two-step method, both ofwhich are set forth below.

Polymers, triclosan, and silver compounds used according to theinvention may be sparingly soluble in certain solvents or solventmixtures. It therefore may be desirable to first dissolve the relevantmaterial in a solvent or component of a solvent system which favorsdissolving. For example, where polyurethane, triclosan, and a silvercompound are desirably incorporated into an alcohol/tetrahydrofuran(“THF”) solvent system, the polyurethane may first be dissolved in THFand the triclosan and silver compound may be dissolved in alcohol (incertain instances with the addition of an aqueous solution of ammonia(referred to interchangeably herein as either ammonia, ammoniumhydroxide, or NH₃) to facilitate solubilization of the silver compound),before the THF and alcohol components are mixed. The use of a solventsystem comprising ammonia may be particularly desirable when a silversalt is used.

4.1 Hydrophilic Article Treated with a Solution of a Hyrdophilic Polymer

In one particular set of non-limiting embodiments, the present inventionprovides for a hydrophilic polymeric medical article (i.e., a medicalarticle fabricated from a hydrophilic polymer) treated by coating,dipping or soaking the article in a treatment solution of a hydrophilicpolymer comprising a silver compound and triclosan (and/or otherchlorinated phenol) wherein the silver compound and triclosan or otherchlorinated phenol are present in amounts such that their combination,in the treated article, has effective anti-microbial activity. The term“effective antimicrobial activity” refers to an ability to decrease thenumber of colony-forming units of a bacterium or yeast, in a 24 hourperiod, by a factor of ten or more and preferably a factor of 100 ormore. The terms “treat”, “treated”, etc., as used herein, refer tocoating, impregnating, or coating and impregnating a medical articlewith anti-infective agent. The term “hydrophilic polymer”, as usedherein, refers to polymers which have a water absorption greater than0.6 percent by weight (and, in preferred embodiments, less than 2percent by weight; as measured by a 24 hour immersion in distilledwater, as described in ASTM Designation D570-81) including, but notlimited to biomedical polyurethanes (e.g., ether-based polyurethanes andester-based polyurethanes, as set forth in Baker, 1987, in ControlledRelease of Biologically Active Agents, John Wiley and Sons, pp. 175-177and Lelah and Cooper, 1986, Polyurethanes in Medicine, CRC Press, Inc.,Florida pp. 57-67; polyurethanes comprising substantially aliphaticbackbones such as Tecoflex™ 93A; polyurethanes comprising substantiallyaromatic backbones such as Tecothane™; and Pellethane™), polylacticacid, polyglycolic acid, natural rubber latex, and gauze orwater-absorbent fabric, including cotton gauze and silk suture material.In specific, non-limiting embodiments, the hydrophilic medical articleis a polyurethane catheter which has been treated with (e.g., coated,dipped or soaked in) a treatment solution comprising (i) between about0.1 and 10 percent, and preferably between about 1 and 5 percent, of oneor more biomedical polyurethane; (ii) between about 0.1 and 5 percent,and preferably between 0.3 and 1.5 percent, of a silver compound; and(iii) between about 0.1 and 20 percent, and preferably between about 0.1and 8 percent, of triclosan and/or other chlorinated phenol.

4.2 Hydrophilic Article Treated with a Solution of a Hyrdophobic Polymer

In another set of particular non-limiting embodiments, the presentinvention provides for a hydrophilic polymeric medical article treatedby coating, dipping or soaking the article in a treatment solution of ahydrophobic polymer comprising a silver compound and triclosan (and/orother chlorinated phenol), wherein the silver compound and triclosanand/or other chlorinated phenol are present in amounts such that theircombination, in the treated article, has effective anti-microbialactivity. The term “hydrophobic polymer”, as used herein, refers to apolymer which has a water absorption of less than 0.6% and includes, butis not limited to, silicone polymers such as biomedical silicones (e.g.,Silastic Type A) or elastomers (e.g., as set forth in Baker, 1987, inControlled Release of Biologically Active Agents, John Wiley and Sons,pp. 156-162), Dacron, polytetrafluoroethylene (“PTFE”, also “Teflon”),polyvinyl chloride (“PVC”), cellulose acetate, polycarbonate, andcopolymers such as silicone-polyurethane copolymers (e.g., PTUE 203 andPTUE 205 polyurethane-silicone interpenetrating polymer). In onespecific, non-limiting embodiment, the medical article is a polyurethanecatheter which has been dipped or soaked in a treatment solutioncomprising (i) between about 0.1 and 10 percent, and preferably betweenabout 1 and 5 percent, of a polyurethane-silicone copolymer; (ii)between about 0.1 and 5 percent, and preferably between about 0.3 and1.5 percent, of a silver compound; and (iii) between about 0.1 and 20percent, and preferably between about 0.1 and 8 percent, of triclosanand/or other chlorinated phenol.

4.3 Hydrophobic Article Treated with a Solution of a Hyrdophobic Polymer

In another set of particular non-limiting embodiments, the presentinvention provides for a hydrophobic polymeric medical article treatedby coating, dipping or soaking the article in a treatment solution ofhydrophobic polymer comprising a silver compound and triclosan and/orother chlorinated phenol, wherein the silver compound and triclosanand/or other chlorinated phenol are present in amounts such that theircombination, in the treated article, has effective antimicrobialactivity. In one specific, non-limiting embodiment, the medical articleis a silicone catheter or a polyvinylchloride catheter which has beendipped or soaked in a treatment solution comprising (i) between about0.1 and 10 percent, and preferably between about 1 and 5 percent, of asilicone polymer; (ii) between about 0.1 and 5 percent, and preferablybetween about 0.3 and 1.5 percent, of a silver compound; and (iii)between about 0.1 and 20 percent, and preferably between about 0.1 and 8percent, of triclosan and/or other chlorinated phenol.

4.4 Hydrophobic Article Treated with a Solution of a Hydrophilic Polymer

In yet another set of particular non-limiting embodiments, the presentinvention provides for a hydrophobic polymeric medical article treatedby coating, dipping or soaking the article in a treatment solution ofhydrophilic polymer comprising a silver compound and triclosan and/orother chlorinated phenol, wherein the silver compound and triclosanand/or other chlorinated phenol are present in amounts such that theircombination, in the treated article, has effective anti-microbialactivity. In a specific, non-limiting embodiment, the medical article isa silicone catheter or Teflon graft which has been dipped, coated orsoaked in a treatment solution comprising (i) between about 0.1 and 10percent, and preferably between about 1 and 5 percent, of a biomedicalpolyurethane polymer; (ii) between about 0.1 and 5 percent, andpreferably between about 0.3 and 1.5 percent, of a silver compound; and(iii) between about 0.1 and 20 percent, and preferably between about 0.1and 8 percent, of triclosan and/or other chlorinated phenol.

4.5 Medical Articles Impregnated with Triclosan and a Silver Compound bya One-step Method

According to the one-step method of the invention, a polymeric medicalarticle may be treated with a solution comprising one or more silvercompounds, triclosan and/or other chlorinated phenol, and optionallycontaining a biomedical polymer, dissolved in one or more solvents,wherein the solvent(s) selected is (are) capable of swelling thepolymeric medical article to be treated; such a solution is referred toherein as an “impregnating solution” (which is a species of treatmentsolution), and the process by which the article is treated withtriclosan and a silver compound is referred to as “impregnation”.Suitable solvents include, but are not limited to, tetrahydrofuran(“THF”), dichloromethane, carbon tetrachloride, methanol, ethanol,methyl ethyl ketone, heptane, M-Pyrol and hexane, and mixtures thereof.The term “reagent alcohol” as used herein refers to a solutioncontaining essentially 5% v/v methanol, 5% v/v isopropanol, and 90% v/vethanol. The biomedical polymer may be hydrophilic or hydrophobic, andincludes the various polymers set forth above.

If a hydrophilic polymeric medical article is to be impregnated with asilver compound and triclosan and/or other chlorinated phenol, theimpregnating solution may, in specific non-limiting embodiments,comprise the following (percentages of solvents in this paragraph beingvolume/volume (v/v) except where noted to be weight/volume (w/v)): 95%ethanol/5% water; 95% reagent alcohol/5% water; 70% ethanol/30% water;70% reagent alcohol/30% water; 50% ethanol/50% water; 50% reagentalcohol/50% water; 30% ethanol/70% THF; 30% reagent alcohol/70% THF; 30%methanol/70% THF; 10% ethanol/10% ammonia/80% THF; 10% reagentalcohol/10% ammonia/80% THF; 90% ethanol/10% THF; 90% reagentalcohol/10% THF; 90% methanol/10% THF; 100% ethanol or 100% reagentalcohol. The treatment solutions may comprise between about 0.1 and 10percent (w/v), and preferably between about 1 and 5 percent (w/v), ofone or more dissolved polymer (e.g., one or more species ofpolyurethane, silicone, or hydrogel). Preferred soaking times accordingto the one-step method vary between 15 seconds and 1 hour, dependingupon the polymer selected. A shorter soaking time in a drug/solventsystem is preferred since it is less likely to negatively affect thephysical integrity of the polymeric device, particularly polyurethanecatheters. In order to attain a sufficient drug uptake using a shortersoaking time, it is preferred that the amount of triclosan or otherchlorinated phenol in the treatment solution be between about 10 and 20percent (w/v). For a specific example of a method that uses higherlevels of triclosan and a shorter soaking time see Section 9 below.

If a hydrophobic polymeric medical article is to be impregnated with asilver compound and triclosan and/or other chlorinated phenol, theimpregnating solution may, in specific non-limiting embodiments,comprise the following (percentages of solvents in this paragraph beingvolume/volume (v/v) except where noted to be weight/volume (w/v)): 10%methanol/90% THF; 10% ethanol/90% THF; 10% reagent alcohol/90% THF; 10%ethanol/10% ammonia/80% THF; 10% reagent alcohol/10% ammonia/80% THF;30% ethanol 70% THF; 30% reagent alcohol/70% THF; 30% methanol/70% THF;1-5 percent (w/v) silicone polymer in 10% methanol/90% THF; 1-5 percent(w/v) silicone polymer in 10% ethanol/90% THF; 1-5 percent (w/v)silicone polymer in 10% reagent alcohol/90% THF; 1-2 percent (w/v)polylactic acid in 10% methanol/90% THF; 1-2 percent w/v polylactic acidin 10% ethanol/90% THF; 1-2 percent (w/v) polylactic acid in 10% reagentalcohol/90% THF; 1-5 percent (w/v) silicone polymer in 30% methanol/70%THF; 1-5 percent (w/v) silicone polymer in 30% ethanol/70% THF; 1-5percent (w/v) silicone polymer in 30% reagent alcohol/70% THF; 1-2percent (w/v) polylactic acid in 30% methanol/70% THF; 1-2 percent (w/v)polylactic acid in 30% ethanol/70% THF; 1-2 percent (w/v) polylacticacid in 30% reagent alcohol/70% THF; 1-5 percent (w/v) silicone polymerin 100% methyl ethyl ketone; and 1-2 percent (w/v) polyurethane in 30%ethanol/70% THF. In general, such treatment solutions may comprisebetween 0.1 and 10 percent, and preferably between about 1 and 5percent, of one or more dissolved polymer. For specific examples, seeSections 11-12, below, and Section 10, which shows examples ofhydrophilic medical articles (e.g., latex urinary catheters) orhydrophobic medical articles (e.g., PTFE soft tissue hernia graftpatches) impregnated with triclosan and silver using a solution withoutpolymer.

The medical article, or a portion thereof, may be immersed in theimpregnating solution to swell, after which the article may be removedand dried at room temperature until all solvent has evaporated and thearticle is no longer swollen. Other methods may also be used, such thata substantially uniform coat of impregnating solution is applied. Duringthe swelling process, triclosan or other chlorinated phenol and silvercompound (and small amounts of polymer when present in the impregnatingsolution) may be distributed within the polymeric substrate of thearticle; during drying, the triclosan or other chlorinated phenol andsilver compound and biomedical polymer (where present) may migratesomewhat toward the surface of the article. In the case of PTFE devices,no apparent swelling occurs, however, the drugs are trapped in theinterstices of the substrate. After drying, the article may be rinsed ineither water or alcohol and wiped to remove any excess triclosan orother chlorinated phenol, silver compound, and/or polymer at thesurface. This may leave a sufficient amount of triclosan or otherchlorinated phenol and silver compound just below the surface of thearticle, thereby permitting sustained release over a prolonged period oftime.

4.6 Two-step Method of Preparing Anti-infective Medical Articles

According to the two-step method of the invention, the one-step methodmay be used to impregnate a medical article with triclosan and/or otherchlorinated phenol and a silver compound, and then the medical articlemay be dipped into a second treatment solution containing triclosanand/or other chlorinated phenol and/or a silver compound and/or one ormore polymer, and dried. This method forms a coating on the article andfurther controls the rate of release of triclosan or other chlorinatedphenol and silver compound. For a non-limiting specific example, seeSection 7, below.

4.7 Medical Articles Having Anti-adherent Properties

It has been discovered that medical articles treated with mixtures ofsilver compounds and triclosan exhibit anti-adherent qualities andanti-microbial effectiveness, even in the absence of chlorhexidine.While not being bound to any particular theory, it is believed thattriclosan and silver compounds form a triclosan-silver compound complex,such that impregnation of this triclosan-silver compound complex intomedical articles increases resistance to microbial adherence to thesurfaces by rendering the surfaces smooth and shiny. It has further beendiscovered that the combination of silver compounds and othercompositions, such as other chlorinated phenolic compounds,anti-inflammatory agents, hydrophilic and hydrophobic polymers andhydrogels each separately contribute to enhanced and prolongedantimicrobial efficacy of the antimicrobial agents. The synergisticcombinations of triclosan and silver compounds that are sparinglysoluble are especially suitable for forming a smooth surface and forproviding a sustained and prolonged release of anti-microbial agents.

In a specific example of a method of direct impregnation of triclosanand a silver compound into a Dacron device, a treatment solution may beprepared including 1 to 6 percent triclosan and 0.1 to 0.2 percent of asilver compound in a solvent mixture containing (v/v) 10 percentammonia, 10 percent alcohol and 80 percent THF. The device may be soakedfor 1 to 10 minutes, dried and rinsed. In variations of this example,between about 1 and 10 percent of a hydrophilic polymer or a hydrophobicpolymer may be included in the treatment solution. Suitable hydrophilicpolymers include, but are not limited to, one or more of polyurethane,polycaprolactone, and polyactic acid. Suitable hydrophobic polymersinclude, but are not limited to, silicone polymers.

4.8 Medical Articles Comprising Triclosan, a Silver Compound, and anAnti-inflammatory Agent

Anti-inflammatory agents such as salicylic acid, paraaminosalicylicacid, and acetylsalicylic acid were impregnated along with triclosan anda silver compound into medical devices to reduce inflammatory reactionaround the wound at the insertion site and thus enhance wound healing.Surprisingly, it has been discovered that incorporation of theseanti-inflammatory agents along with the triclosan and a silver compoundenhances the anti-microbial activity of the composition. Since theanti-inflammatory agents do not give zones of inhibition when usedalone, it appears that increased zone sizes, observed when theanti-inflammatory agents are added to the triclosan and silver compoundcombination, is not a result of an additive effect but rather due topotentiation of the activity of the complex. Thus, the present inventionprovides for medical articles treated with treatment solutionscomprising triclosan and/or other chlorinated phenol, a silver compound,and an anti-inflammatory agent, such as salicylic acid or a derivativethereof. In further non-limiting embodiments, the treatment solution mayalso include an additional anti-infective agent such as those set forthbelow, or chlorhexidine, or a chlorhexidine salt (at a concentration ofbetween about 0.1 and 5 percent).

4.9 Addition of other Anti-infective Agents

Because a major route of entry of pathogens during implantation ofmedical devices occurs at the insertion site and occurs at the time ofimplantation, it is important to have an effective broad spectrumantimicrobial field around the device during implantation. In order toenhance the antimicrobial field around a device, antibiotic andanti-microbial agents may be added to medical articles comprisingtriclosan or other chlorinated phenol and a silver compound including,but not limited to, macrolides, aminoglycosides, penicillins,cephalosporins, quinolones, antifungal agents, chlorhexidine orbiguanides other than chlorhexidine, chlorinated phenols, sulfonamides,quarternary ammonium compounds, picloxydine, phenolic compounds (e.g.,orthophenylphenol), and polymeric quarternary ammonium compounds.Examples of specific agents which can be used include rifampicin,gramicidin, gentamycin, fusidic acid, miconazole, norfloxacin,polymixin, sulfamylon, furazolidine, alexidine, octenidinehydrochloride, cetrimide, polyhexamethylene biguanide, triclocarban,benzalkonium chloride, minocycline, iodine and iodine complexes such aspovidone iodine, pluroniciodine complex, benzoic acid, sorbic acid, andethylenediamine tetraacetic acid (EDTA).

These agents used in addition to the triclosan and/or other chlorinatedphenol and silver compound combination provide an effective broadspectrum anti-microbial field of activity initially, which inactivatespathogens that otherwise can heavily contaminate the sterile fieldduring implantation. For a non-limiting specific example, see Section15.

The anti-adherent surface of these devices continues to preventadherence of microbes that may enter the device tract during andsubsequent to implantation. Once these additional agents are diffusedout of the devices, the anti-adherent surface continues to preventadherence of microbes which may contact the device surface throughhematogenous seeding or contaminated infusate. Further, without beingbound to any particular theory, it is believed that sustained andprolonged release of the anti-microbial agents occurs from the putativetriclosan-silver compound complex which provides a longer period ofprotection.

4.10 Medical articles Comprising a Hydrogel

According to the present invention, it has been determined that the useof hydrogel polymers increases the antimicrobial efficacy of hydrophilicor hydrophobic matrix systems. In a particular embodiment, the presentinvention provides for a hydrophilic or hydrophobic medical articlewhich has been impregnated, coated or impregnated and coated with atreatment solution comprising (i) a hydrophilic or hydrophobic polymer,(ii) one or more metal compounds comprising metal atoms or ions orcomplexes comprising a metal atom or ion selected from the groupconsisting of silver, copper, zinc, calcium, aluminum and magnesium,(iii) triclosan or other chlorinated phenol, and (iv) a hydrogel. Suchmedical articles may further comprise, or the treatment solution maycomprise, a biguanide such as chlorhexidine or a chlorhexidine salt. Inother embodiments, the present invention provides for a metallic orceramic medical article coated with a treatment solution of (i) to (iv)as set out above. In a preferred embodiment, the hydrogel comprisespolyvinyl pyrrolidone (“PVP”). In another preferred embodiment, thehydrophobic polymer polyvinyl chloride (“PVC”) may be used to create ahydrophobic matrix into which PVP and antimicrobial agents may beimpregnated. Other useful hydrogels that may be used to promote enhancedantimicrobial efficacy include polyethylene oxide, pluronics, ethyl andmethyl cellulose, hydroxy ethyl and hydroxy methyl cellulose,incroquats, and polyhydroxyethyl methacrylate.

For a specific, non-limiting example, see Section 19, below.

The following working examples are intended to illustrate but not tolimit the scope of the present invention.

5.0 EXAMPLE Triclosan Improves the Solubility of Silver Compounds

Table 1 illustrates the solubility of the silver salt, silver carbonate,mixed at various molar ratios with ammonia, which is used in a treatmentsolution, in the absence and the presence of triclosan at various molarratios. Table 2 illustrates the solubility of the silver salt, silveroxide, mixed at various molar ratios with ammonia in the absence andpresence of triclosan at various molar ratios. The solubility resultsdemonstrated in Tables 1 and 2 indicate that silver salts are much moresoluble in the presence of triclosan, which suggests that the silvercompound and triclosan may form a complex.

When ammonia and silver carbonate were mixed at a high molar ratio of400 to 10, the silver salt remained insoluble in the solvent system. Incontrast, in the presence of 30 μmole of triclosan, the molar ratio ofammonia to silver carbonate needed to solubilize was 50 to 10. Achievinga low molar ratio of ammonia to silver salt is preferred because thesurface of devices impregnated with a solvent system containing higheramounts of ammonia can be damaged, thereby enhancing the likelihood ofmicrobial adherence to the surface. In the case of silver oxide, only 10μmole of ammonia was needed to solubilize more than 90% of 10 μmole ofsilver oxide in the presence of 10 μmole of triclosan. Further, only 20μmole of triclosan was needed to completely solubilize 10 μmole ofsilver oxide in the presence of only 10 μmole of ammonia.

TABLE 1 Silver Carbonate Ammonia Triclosan (μmole) (μmole) (μmole)Solubility 10 100 0 Not Soluble 10 200 0 Not Soluble 10 300 0 NotSoluble 10 400 0 Not Soluble 10 0 30 Not Soluble 10 50 10 PartiallySoluble 10 100 10 Partially Soluble 10 150 10 Soluble 10 75 20 PartiallySoluble 10 50 30 Soluble

TABLE 2 Silver oxide Ammonia (μmole) (μmole) TC (μmole) Solubility(μmole) 10 10 0 Not soluble 10 100 0 Soluble 10 10 10 >90% Soluble 10 1020 Soluble

6.0 EXAMPLE Evaluation of the Anti-microbial Efficacy ofTriclosan-silver Compound Combinations in Broth Cultures

The synergistic anti-microbial efficacy of the triclosan/silver compoundcombination, triclosan/silver sulfadiazine, is illustrated by theresults shown in Table 3, and were determined by the following protocol.Drug solutions containing 10% ammonia were prepared in ethanol, and 0.1ml of each solution was added to 0.9 ml of bacterial culture (50%trypticase soy broth +50% Bovine Calf Serum containing 10⁸ cfu S.aureus/ml). After 10 minutes, a 0.1 ml aliquot was removed and added to0.9 ml drug inactivating media (LTSB). 0.1 ml from this media was thenadded to another 0.9 ml of LTSB and 0.2 ml was subcultured on trypticasesoy agar plate and incubated at 37° C. for 24 hours. The colony countswere then determined. Control cultures contained similar amounts ofammonia and ethanol as in the test culture.

TABLE 3 Solution Growth in Culture Triclosan (%) Silver Sulfadiazine (%)(cfu/ml) 0 0 2.1 × 10⁷ 0.25 0 1.2 × 10⁷ 0.5 0   1 × 10⁷ 0 0.5   5 × 10⁶0 1.0 1.5 × 10⁶ 0.5 0.5 8.3 × 10⁵ 0.5 1.0 1.4 × 10⁴

These results show the synergistic activity of triclosan and silversulfadiazine. In the control, in the absence of either triclosan orsilver sulfadiazine, there was growth in culture of the magnitude of2.1×10⁷ cfu/ml. Comparing the relative reduction of growth in culture bythe introduction of triclosan and silver sulfadiazine, the addition oftriclosan alone at 0.25 and 0.5 percent each resulted in a reduction ingrowth in culture of less than a power of 10 compared to the control.The addition of silver sulfadiazine alone at 0.5 and 1.0 percent eachresulted in a 1 log reduction of growth in culture compared to thecontrol.

Comparing the relative reduction of growth in culture by theintroduction of triclosan and silver sulfadiazine in combination, thecombination of 0.5 percent triclosan and 0.5 percent silver sulfadiazineresulted in a 2 log reduction in growth in culture compared with thecontrol. The combination of 0.5 percent triclosan and 1.0 percent silversulfadiazine resulted in a 3 log reduction in cell growth in culturecompared with the control. Moreover, the addition of 0.5 percent ofsilver sulfadiazine from 0.5 to 1.0 in the presence of 0.5 triclosanresulted in a 1 log reduction in growth in culture, whereas the increaseof 0.5 to 1.0 percent silver sulfadiazine in the absence of triclosandid not result in a significant decrease. The cell growth in culture inthe presence of 0.5 percent triclosan alone added to the cell growth inculture in the presence of 0.5 percent of silver sulfadiazine, thecombined presence of 0.5 triclosan and 1.0 silver sulfadiazine resultedin a 3 log reduction in growth in culture, and the increase of 0.5 to1.0 percent silver sulfadiazine compared to the growth in culture at 0.5percent triclosan results in a 1 log decrease.

The effects of triclosan and silver carbonate combinations on S. aureusgrowth in culture were also determined using the same protocol. Theresults are presented in Table 4.

TABLE 4 Solution Growth in Culture Triclosan (%) Silver Carbonate (%)(cfu/ml) 0 0   5 × 10⁷ .25 0   2 × 10⁷ .5 0 1.2 × 10⁷ 0 .06   1 × 10⁵ 0.125   2 × 10³ 0 .25   5 × 10² .5 .06 3.2 × 10⁴ .5 .125 0 .5 .25 0

The results shown in Table 4 illustrate the synergistic activity oftriclosan and silver carbonate. In the control, in the absence of bothtriclosan and silver carbonate the growth in cell culture was of themagnitude of 5×10⁷ cfu/ml. Combining 0.5 percent triclosan and 0.25percent silver carbonate resulted in a 7 log reduction in growth inculture. The addition of 0.5 percent triclosan alone resulted in a 0 logreduction, and the addition of 0.25 silver carbonate alone resulted in a5 log reduction. Therefore one would expect a 5 log reduction of growthin cell culture upon combining the two compositions. However, due to asynergistic activity present when triclosan is combined with silvercarbonate an additional 2 log reduction was observed.

Alone, 0.06 percent and 0.125 percent silver carbonate caused a 2 logand a 4 log reduction in growth in culture, respectively, and 0.5percent triclosan alone caused a 0 log reduction. However, 0.06 percentand 0.125 percent silver carbonate each combined with 0.5 percenttriclosan resulted in, respectively, a 3 log reduction and a 7 logreduction of growth in culture.

7.0 EXAMPLE Anti-imicrobial Efficacy of Catheters Impregnated with (1)Triclosand Silver Salts and Various Organic Acid and (2) Triclosan,Silver Salts, and Chlorhexidine

Catheters impregnated with triclosan, silver compounds and variousorganic acids, with and without chlorhexidine, were evaluated foreffectiveness and duration of antimicrobial efficacy. Treatmentsolutions comprising triclosan, a silver compound, and an organic acidor chlorhexidine as well as polyurethane polymers were prepared by firstdissolving the triclosan, silver compound, and acid or chlorhexidine inmethanol, dissolving the polymers in THF, and then mixing the methanolsolution with the THF solution in a 30% v/v methanol solution/70% v/vTHF solution solvent system. Polyurethane central venous cathetersegments were then dipped for one minute in the treatment solution, thenallowed to dry. The final concentrations (percentages based on w/v) ofactive agents and polymers in the treated catheters are set forth inTable 5.

In related experiments, polyurethane catheter segments were treated by atwo-step process. In the first step, catheters were dipped in a 70% v/vTHF+30% v/v reagent alcohol treatment solution having finalconcentrations of 3% w/v 93A polyurethane and 1% 60D polyurethane,either with or without silver carbonate at a final concentration of 0.6%(the various components were dissolved in either THF or reagent alcoholbefore mixing the two to produce the treatment solution, as set forthabove). The catheters were allowed to dry. Then, in the second step, thecatheters were soaked for one minute in a 20% v/v THF+80% v/v methanolsolvent mixture containing either triclosan alone, triclosan and citricacid, or triclosan and chlorhexidine at concentrations set forth inTable 6.

The zones of inhibition were studied against S. epidermidis and P.aeruginosa over a two day period. The results, shown in Tables 5 and 6,indicate that the combination of citric acid, triclosan and silvercompound (silver carbonate) resulted in superior antimicrobial activityagainst Pseudomonas aeruginosa, compared to other organic acids tested.

TABLE 5 Zones of Inhibition (mm) S. epidermidis P. aeruginosa TreatmentSolution Day 1 Day 2 Day 1 Day 2 6% TC + 0.6% Ag₂CO₃ + 3% 20 18 9 0 93APU + 1% 60D PU 6% TC + 0.6% Ag₂CO₃ + 2% 20 18 11 0 salicylic acid + 3%93A PU + 1% 60D PU 6% TC + 0.6% Ag₂CO₃ + 2% 20 18 8 0 mandelic acid + 3%93A PU + 1% 60D PU 6% TC + 0.6% Ag₂CO₃ + 2% 20 18 8 0 deoxycholic acid +3% 93A PU + 1% 60D PU 6% TC + 0.6% Ag₂CO₃ + 2% 20 19 11 8 citric acid +3% 93A PU + 1% 60D PU 6% TC + 0.3% Ag₂CO₃ + 2% 21 20 13 12 CHX + 3% 93APU + 1% 60D PU

TABLE 6 Zones of Inhibition (mm) S. epi- P. dermidis aeruginosa FirstStep Treat- Second Step Day Day Day Day ment Solution Treatment Solution1 2 1 2 3% 93A PU + 1% 6% TC + 4% Citric Acid 20 18  0  0 60D PU 3% 93APU + 1% 6% TC 20 18  9  0 60D PU + 0.6% Ag₂CO₃ 3% 93A PU + 1% 6% TC + 4%Citric Acid 20 18 10  7 60D PU + 0.6% Ag₂CO₃ 3% 93A PU + 1% 6% TC + 2%CHX 21 17 12 11 60D PU

8.0 EXAMPLE Methods of Preventing Adherence on Medical Articles

The following techniques were used to impregnate 93A polyurethanecatheter segments with triclosan and various silver compounds. Theresulting surface characteristics, scored on a scale of 1 to 4, with 4being the most lubricious surface, are shown in Tables 7 and 8. Soakingtime varied from 15 seconds to 1 hour.

Method A: The outer surfaces of catheter segments were impregnated bydipping the segments in a treatment solution of 70% v/v THF (containing93A polyurethane and 60D polyurethane)+30% v/v (2:1 reagentalcohol:ammonia containing triclosan and silver compound), having finalconcentrations of 3% w/v 93A polyurethane, 1% w/v 60D polyurethane, 0.3%w/v silver atom or ion, and 6% w/v triclosan.

Method B: Catheter segments had their ends sealed and were soaked for 5minutes in a treatment solution of 90% v/v (8:1 reagent alcohol/ammoniacontaining triclosan and silver compound)+10% THF, having finalconcentrations of 6% w/v triclosan and 0.3% silver (atom or ion).

Method C: The ends of the catheter segments were sealed and the segmentswere dipped in a treatment solution of 70% v/v THF (containing 60Dpolyurethane)+30% v/v reagent alcohol having a final concentration of 2%w/v 60D polyurethane. The catheter segments were then dried for onehour, and then were soaked for 5 minutes in a treatment solution of 90%v/v (8:1 ethanol/ammonia containing triclosan and silver compound)+10%THF, having final concentrations of 6% w/v triclosan and 0.3% silver(the treatment solution used in Method B).

Method D: Catheter segments were dipped in a treatment solution of 70%v/v THF (containing 93A polyurethane and 60D polyurethane)+30% v/v (2:1reagent alcohol:ammonia containing a silver compound), having finalconcentrations of 3% w/v 93A polyurethane, 1% w/v 60D polyurethane, and0.3% w/v silver (atom or ion) (the treatment solution used in Method A,but without the triclosan).

The surface characteristics of catheter segments treated according toMethods A-D are shown in Table 7.

TABLE 7 Surface Characteristics Silver Salt A B C D 0 (only triclosan) 33 4 — Silver carbonate 4 4 4 3 Silver deoxycholate 4 4 4 Rough Silveroxide 4 4 4 3 Silver salicylate 4 4 4 2 Silver iodide 3 3 3 2 Silversulfadiazine 3 2 2 2 Silver nitrate 4 4 4 4

Table 8 shows the results when the outer surfaces of catheter segmentswere impregnated by dipping the catheters in a treatment solution of 70%v/v THF (containing 93A and 60D polyurethanes) and 30% v/v reagentalcohol (containing triclosan, an organic acid, and a silver compound),having final concentrations of 3% w/v 93A polyurethane, 1% w/v 60Dpolyurethane, 0.3% w/v silver (atom or ion), 6% w/v triclosan, and 1%w/v organic acid.

TABLE 8 Metal Salts and Acid in TC Complex Surface CharacteristicsSilver carbonate + salicylic acid 3.5 Silver carbonate + deoxycholicacid 3.5 Silver sulfadiazine + salicylic acid 3 Silver sulfadiazine +deoxycholic acid 3 Silver carbonate + citric acid 4 Silversulfadiazine + citric acid 4 Silver sulfadiazine + palmitic acid 3.5Silver sulfadiazine + propionic acid 3.5 Silver sulfadiazine + asparticacid 3.5

9.0 EXAMPLE Anti-microbial Polyurethane Catheters Prepared by a ShorterSoaking Time (15 seconds) and Higher Triclosan Levels (up to 15%) in theImpregnation Solution

A shorter soaking time is preferred in a drug/solvent system since it isless likely to negatively affect the physical integrity of a polymericdevice, particularly a polyurethane catheter. In order to attainsufficient drug uptake using a shorter soaking time, it is preferred toincrease the amount of triclosan in solution to a range of 10% to 15%.For example, polyurethane catheters were dipped in a solution containing2% 60D polyurethane dissolved in 70% THF+30% reagent alcohol and allowedto dry for 1 hour. They were then soaked for 15 seconds in a solutionprepared by dissolving enough triclosan and AgNO₃ in an 8:1 reagentalcohol/ammonia solution such that when a treatment solution wasprepared containing 10% THF and 90% of the reagentalcohol/ammonia/triclosan/AgNO₃, the treatment solution contained 15%triclosan and 0.48% AgNO₃. As a comparison, catheters were prepared asabove with the following changes: the triclosan concentration wasreduced to 6% and the soaking time was increased to 1 minute. Theinitial drug levels, measured spectrophotometrically, and zones ofinhibition against S. epidermidis and P. aeruginosa were determined forcatheter samples of both groups and are shown in Table 9.

TABLE 9 Zones of Inhibition (mm) vs. S. vs. P. Treatment μg TC/cmepidermidis aeruginosa 15 sec × (15% TC + 436 11 4 0.48% AgNO₃) 1 mm ×(6% TC + 410 13 4 0.48% AgNO₃)

As illustrated in Table 9, both initial drug uptake and zone ofinhibition data indicate that a similar efficacy is obtainable using ahigher concentration of drug and a shorter soaking time. In addition, ashorter soaking time in a drug/solvent system is less likely tonegatively affect the physical integrity of the device.

10.0 EXAMPLE Impregnation of Triclosan-silver Combination in LatexUrinary Catheter and PTFE Soft Tissue Patches (STP)

Segments of latex urinary catheters and PTFE soft tissue patches (STP)were impregnated by soaking these materials (or suctioning under vacuumin the case of PTFE STP) for 1 hour in a treatment solution prepared bymixing 80% v/v THF and 10% v/v reagent alcohol/10% v/v ammonia(containing triclosan and silver carbonate), having final concentrationsof 1% w/v triclosan and 0.2% w/v silver carbonate. The impregnatedmaterials were dried and then rinsed in water and dried again. Theantimicrobial properties of the material were then tested by measuringthe zones of inhibition produced against S. aureus, P. aeruginosa, E.aerogenes and C. albicans after placing the treated material on atrypticase soy agar plate seeded with 0.3 ml of 10⁸ cfu/ml bacterial oryeast culture and incubating at 37° C. for 24 hours. The results areshown in Table 10.

TABLE 10 Zones of inhibition (mm) Urinary Catheter STP S. aureus 21 >30P. aeruginosa 6 7 E. aerogenes 10 25 C. albicans 7 12

11.0 EXAMPLE Antimicrobial Efficacy of Subcutaneous Cuffs ContainingFabrics Consisting of Dacron, Acrylic and PTFE

The antimicrobial efficacy of subcutaneous cuff material containingfabrics made of Dacron, Acrylic and PTFE were impregnated with atreatment solution prepared by mixing 10% v/v ammonia/10% v/v reagentalcohol (containing silver carbonate, triclosan and chlorhexidine) and80% v/v THF (containing 93A and 60D polyurethanes), having finalconcentrations of 4% w/v 93A polyurethane, 1% w/v 60D polyurethane, 0.2%w/v silver carbonate, 0. 1% w/v triclosan and 0.5% w/v chlorhexidine,The resulting material was then dried for 24 hours and the zones ofinhibition against S. aureus and P. aeruginosa were determined. Thezones of inhibition are shown in Table 11.

TABLE 11 Zone of Inhibition (mm) Cuff Material S. aureas P. aeruginosaDacron 20 12 Acrylic 19 12 PTFE 18 10

12.0 EXAMPLE Method of Impregnation of Left Ventricular Assist Device(LVAD) Drive Lines

Left ventricular assist device (LVAD) drive lines, which are made ofDacron material and are attached to silicone tubing, were impregnatedwith a polymeric matrix containing triclosan and silver salts.

Dacron material was treated with one of two different treatmentsolutions as follows.

In a first case, Dacron material was uniformly spread with a treatmentsolution which was 10% v/v ammonia, 10% v/v reagent alcohol (containingsilver carbonate and triclosan)+80% THF (containing 93A and 60Dpolyurethanes), having final concentrations of 0.2% w/v silvercarbonate, 0.1% w/v triclosan, 4% w/v 93A polyurethane, and 1% w/v 60Dpolyurethane. As in previous examples, the silver carbonate andtriclosan were first dissolved in 1:1 ammonia/reagent alcohol, and thepolyurethanes were first dissolved in THF, and then the ammonia/reagentalcohol and THF were mixed to achieve the proper final ratios.

In a second case, Dacron material was uniformly spread with a treatmentsolution which was 10% v/v ammonia, 10% v/v reagent alcohol (containingsilver carbonate, triclosan and chlorhexidine)+80% THF (containing 93Aand 60D polyurethanes), having final concentrations of 0.2% w/v silvercarbonate, 0.5% w/v chlorhexidine, 0.1% w/v triclosan, 4% w/v 93Apolyurethane, and 1% w/v 60D polyurethane.

Dacron material having a polymer-drug film prepared as above was thenattached to silicone tubing, thereby creating a drive line, and dried.This method is particularly important for devices in which tissueingrowth is intended to occur after implantation (e.g., cuffs).Antimicrobial activity was evaluated after 24 hours by measuring thezones of inhibition produced by placing 0.25 cm length of drive line ontrypticase soy agar seeded with 0.3 ml of 10⁸ cfu/ml bacteria andincubated at 37° C. for 24 hours. The zones of inhibition were measuredafter 24 hours, and the results are shown in Table 12.

TABLE 12 Zones of Inhibition (mm) Drugs in Catheter S. aureus P.aeruginosa 0.2% Ag₂CO_(3,) 0.1% TC 16  6 0.2% Ag₂CO_(3,) 0.1% TC, 0.5%CHX 20 12

As shown in Table 12, drive line treated with polymer, silver carbonate,and low levels of triclosan had antimicrobial activity against both S.aureus and P. aeruginosa. The antimicrobial effect was improved by theaddition of chlorhexidine.

In related experiments, subcutaneous cuffs containing fragmentsconsisting of Dacron, acrylic or PTFE were impregnated by dipping in atreatment solution which is 10% v/v ammonia, 10% v/v reagent alcohol(containing silver carbonate, triclosan and chlorhexidine)+80% THF(containing 93A and 60D polyurethanes), having final concentrations of0.2% w/v silver carbonate, 0.5% w/v chlorhexidine, 0.1% w/v triclosan,4% w/v 93A polyurethane, and 1% w/v 60D polyurethane. The treatedmaterial was allowed to dry, and then tested for antimicrobial activityas set forth above. The results are shown in Table 13.

TABLE 13 Zone of Inhibition (mm) Cuff Material S. aureas P. aeruginosaDacron 20 12 Acrylic 19 12 PTFE 18 10

13.0 EXAMPLE Bacterial Adherence on Triclosan-silver CompoundImpregnated Catheters Post Implantation in Rats

The ability of catheters impregnated with triclosan and a silvercompound to resist bacterial adherence was tested by introducing andmaintaining treated catheters in vivo in rats, removing the catheters,exposing the catheters to bacterial cultures, and then measuring theamount of bacteria adhered to the extracted catheter segments.

The catheter segments were impregnated with triclosan and various silvercompounds and/or chlorhexidine diacetate (CHA), using treatmentsolutions having the final concentrations of agents set forth in Table14, below. In each case, the amount of silver compound in the treatmentsolution contributed silver atom/ion at a concentration of 0.3% w/v. Thetreatment solutions comprised THF and reagent alcohol mixed solutions,where polyurethane components were dissolved in the THF and triclosanand silver compounds were dissolved in the reagent alcohol prior tomixing. The amount of THF/polyurethane was generally 70% (v/v). Theamount of reagent alcohol was 30% (v/v). Where indicated by an asteriskin Table 16, the solvent was simply reagent alcohol; otherwise, thesolvent system was reagent alcohol/ammonia in a 2:1 ratio (accountingfor 20% and 10%, respectively, on a volume to volume basis). Polymers inthe treatment solutions were initially dissolved in the THF componentand had final concentrations of 3% w/v 93A polyurethane and 1% w/v 60Dpolyurethane. Catheter segments were dipped in the treatment solution,and then dried for three days prior to use. Unimpregnated cathetersegments were used as controls.

Six 3 cm segments of catheters from each catheter group were implantedin a subcutaneous pocket on the dorsal side of laboratory rats. Afterseven days the catheters were removed and rinsed twice in saline andprocessed as follows: Each group of catheter segments (6×3 cm) weretransferred to 18 ml of 10% BCS+90% TSB containing 3.0 ml of 10⁷ cfu S.epidermidis/ml at 37° C. in a rotary shaker for 4 hours. Then thecatheters were removed, blotted, rinsed twice in saline, blotted androlled over the surface of drug neutralizing agar plates (D/E plates)and incubated for 24 hrs at 37° C. The colony counts observed in Table14 were then determined for each catheter group.

TABLE 14 Agents No. of Catheter Segments in Treatment Catheter SegmentsColonized (10²-10⁴ Solution Not Colonized cfu/cm) 6% TC + 0.75% 0 6 AgSD6% TC + 0.79% 0 6 Ag paraamino salicylic acid 6% TC + 0.8% 0 6 Agacetylsalicylic acid 0.75% AgSD + 0 5 4% CHA* 6% TC + 0.6% 1 5 Agsalicylate 6% TC + 0.8% 1 5 Ag laurate 6% TC + 1.5% 1 5 Ag deoxycholate6% TC 1 4 6% TC + 0.32% 2 4 Ag oxide 6% TC + 1% Ag 3 3 Paraamino benzoicacid 6% TC + 0.4% 4 2 Ag Carbonate 6% TC + 0.48% 5 1 Ag Nitrate 6% TC +0.4% 5 1 Ag Carbonate* control 1 0 4 control 2 1 5 *solution does notcontain ammonia

As evidenced from the results of Table 14, the catheter groupscontaining triclosan-silver salt combinations were effective inpreventing bacterial adherence on catheters after being implanted forseven days in rats.

A further two sets of experiments were carried out to determine theantimicrobial efficacy of catheters treated according to the invention.In particular, one set of experiments involved an “initial infectionmodel” where the initial catheter wound site was inoculated withbacteria, and another set of experiments involved a “delayed infectionmodel” in which catheters implanted in rats for ten days were removedand exposed to bacterial cultures in vitro. In these two sets ofexperiments, the results of which are shown in Table 15, long term andshort term efficacy of treated catheters was evaluated and compared.

In experiments involving the “initial infection model”, the dorsal sideof a rat was shaved and a 7 cm segment of catheter treated with theagents set forth in Table 15 (with both ends sealed with silicone plugs)was implanted subcutaneously through a 0.5 cm incision just above theshoulder area. The catheter was kept in place, and the tract andinsertion site were inoculated with 20 μl of bacterial culture having10⁸ cfu of S. aureus per milliliter. The wound was then closed withsurgical clips. After ten days, the catheters were removed and swabcultures of the insertion site and tract were taken. Only the controlgroup had a positive swab culture. Bacterial adherence on the outersurface of the catheters was determined by sonicating the catheters indrug neutralizing media and then subculturing on a trypticase soy agarplate.

In experiments involving the “delayed infection model”, cathetersegments (3 cm each, with sealed ends, treated with the agents set forthin Table 15, in solvent systems that were 70% v/v THF and 30% v/vreagent alcohol and contained 3% w/v 93A and 1% w/v 60D polyurethanes)were implanted subcutaneously in rats (6 segments of catheters treatedwith the same agents per rat). After ten days in vivo, the catheterswere excised and rinsed twice with saline. Then each group of sixsegments was incubated in 18 ml of a log-phase culture of S. epidermidis(10⁷ cfu/ml of 10% bovine adult serum+90% TSB) in a rotary shaker forfour hours. The bacterial adherence was determined by sonicating thecatheters in drug neutralizing media and then subculturing on atrypticase soy agar plate.

Untreated catheters were implanted in rats of both models to serve ascontrols.

TABLE 15 10 Days Initial Post Catheter Group Contamination*Contamination* Control 1 × 10³ >10⁵ 1.5% CHA + 0.75% AgSD 10 5 × 10⁵ 2%CHA + 2% TC + 0.75%  0 1 × 10⁴ AgSD 6% TC + 0.36% AgNO₃ 33 26 6% TC +0.4% Ag₂CO₃ 90 1 × 10² 6% TC + 0.75% AgSD Not Done 1 × 10⁴ *colonyforming units (cfu) per 1 cm catheter.

As shown in Table 15, triclosan/silver nitrate and triclosan/silvercarbonate treated catheter surfaces were found to be more lubricious (asindicated by lower cfu associated with catheters 10 dayspost-implantation), even though their antimicrobial activity appeared tobe lower than that of chlorhexidine/silver sulfadiazine orchlorhexidine/triclosan/silver sulfadiazine treated catheters (asreflected by lower cfu in the initial contamination models). It appearsfrom these results that surface characteristics play an important rolein the prevention of delayed infection. Chlorhexidine containingcatheters were more effective in preventing initial infections whiletriclosan/silver compound catheters were more effective in preventinglater infections. The latter catheters showed significantly lowerbacterial adherence compared to control catheters when infectedinitially.

14.0 EXAMPLE Ability of Treated PTFE Patches to Resist Infection in anAnimal Model

The ability of PTFE soft tissue patches, treated with combinations oftriclosan and/or chlorhexidine and the silver salt, silver carbonate, toresist infection was tested as follows. Disks of PTFE patches wereimpregnated with treatment solutions prepared by dissolving triclosanand/or chlorhexidine and silver carbonate in 1:1 reagentalcohol/ammonium hydroxide, and then mixing with THF to produce a 80%v/v THF, 10% reagent alcohol, 10% v/v ammonium hydroxide solution havingtriclosan, chlorhexidine, and silver carbonate final concentrations asspecified in Table 16 below. The patch material was soaked in treatmentsolution for 1 hour under a vacuum. The patches were implantedsubcutaneously in a pocket in the abdominal area of rats and infectedwith 10 μl of 10⁸ CFU S. aureus. After 7 days, they were removed andbacterial adherence was determined by sonicating the catheters in drugneutralizing media and then subculturing on a trypticase soy agar plate.The efficacy of patches in resisting infection due to contamination atthe time of implantation is illustrated by the bacterial adherence dataprovided in Table 16.

TABLE 16 Bacterial Adherence Impregnation Solution CFU/DISK 0.25% TC +0.2% Ag₂CO₃ + 0.5 CHX  4 1.0% TC + 0.2% Ag₂CO₃  1 0.5% CHX + 0.2% Ag₂CO₃15 0.5% TC + 0.25% CHA + 0.25% CHX 15 Unimpregnated 7.6 × 10³

As shown in Table 16, all of the above groups with and withoutchlorhexidine were observed to be similarly efficacious relative to thecontrol, unimpregnated group.

15.0 EXAMPLE Enhancement of the Anti-microbial Activity of DevicesContaining Silver and Triclosan Using other Soluble Anti-infectiveAgents

Polyurethane catheter segments were impregnated by dipping in atreatment solution prepared by mixing 10% v/v ammonia/20% v/v reagentalcohol (containing triclosan, silver carbonate, and, except for thecontrol, an additional antibiotic) with 70% v/v THF (containing 93A and60D polyurethanes), having final concentrations of 3% w/v 93Apolyurethane, 1% w/v 60D polyurethane, 6% w/v triclosan, 0.4% w/v Ag₂CO₃and 0.5% of the antibiotics set forth in Table 17, below. The treatedcatheter segments were then dried for 24 hours and evaluated forantimicrobial activity by determining the zones of inhibition created incultures of various microbes. The antimicrobial properties of thematerial were then tested by measuring the zones of inhibition producedagainst S. aureus, P. aeruginosa, E. aerogenes and C. albicans afterplacing the treated material on a trypticase soy agar plate seeded with0.3 ml of 10⁸ cfu/ml bacterial/yeast culture and incubating at 37° C.for 24 hours.

Table 17 shows the enhanced effective broad spectrum anti-microbialfield around a catheter produced by the addition of solubleanti-infective agents. Using antibiotics along with the triclosan-silversalt combination may reduce the risk of development of antibioticresistant microbes.

TABLE 17 Agents in Treatment Zones of Inhibition (mm) Solution S. aureusP. aeruginosa E. aerogens C. albincans 6% TC + 0.4% 14  6  7  7 Ag₂CO₃ +0.5% Gram- icidin 6% TC + 0.4% 17 16 15  7 Ag₂CO₃ + 0.5% Poly- mixin 6%TC + 0.4% 19 18 18 10 Ag₂CO₃ + 0.5% Nor- floxacin 6% TC + 0.4% 12 12 13 9 Ag₂CO₃ + 0.5% Sulf- amylon 6% TC + 0.4% 21  5  5  0 Ag₂CO₃ + 0.5%Rif- ampincin 6% TC + 0.4% 13  6  6  5 Ag₂CO₃ + NO ANTI- BIOTIC(CONTROL)

16.0 EXAMPLE Antimicrobial Activity of Various Triclosan-silver CompoundCombinations

Polyurethane catheter segments were treated by dipping in a treatmentsolution having final concentrations of triclosan and/or silver compoundas set forth in Table 18, below, where the solvent system was 70% v/vTHF and 30% v/v reagent alcohol and contained 3% w/v 93A and 1% w/v 60Dpolyurethanes. Six catheter segments from each group were placedvertically on a trypticase soy agar plate seeded with 0.3 ml of 10⁸cfu/ml bacterial/yeast culture and incubated at 37° C. for 24 hours. Theresults are shown in Table 18.

TABLE 18 Drug in Zones of Inhibtion (mm) Impregnation EnterobacterCandida Solution S. aureus P. aeruginosa aerogenes albicans 6% TC 15 0 60 1% AgSD 8 5 0 0 0.5% Ag₂CO₃ 8 7 0 6 0.6% Ag- 9 6.5 0 7.3 Salicylate0.32% Ag 9 7 0 11 Oxide 1.5% Ag 1 4 0 5 Deoxycholate 6% TC + 1% 17 6 5 5AgSD 6% TC + 0.5% 22 9 6 7 Ag₂CO₃ 6% TC + 0.6% 20 10 7 11 Ag Salicylate6% TC + 0.32% 22 10 6 15 Ag Oxide 6% TC + 1.5% 17 7 5 10 Ag Deoxycholate2% TC + 1% 17 11 12 13 AgSD + 2% CHX 6% TC + 0.7% 17 7 6 5 Ag ParamminoBenzoate acid 6% TC + 0.79% 19 7 6 4 Ag Paraamino Salicylate 6% TC +0.8% 19 8 7 9 Ag Acetyl- Salicylate 0.7% Ag 3.5 4.0 0 0 ParaaminoBenzoate 0.79% Ag 5.5 7.5 3.3 0 Paraamino Salicylate 0.8% Ag 7.0 8.0 4.70 Acetyl Salicylate

It is noted that the combination of triclosan with either silverparaaminobenzoate, silver paraaminosalicylate, or silveracetylsalicylate resulted in unexpected efficacy against C. albicans ascompared with each of the agents tested alone. Also illustrated by Table18 is the synergistic effect achieved by the presence of triclosan incombination with silver salts.

17.0 EXAMPLE Impregnation of Anti-inflammatory Agents Along withTriclosan and Silver Salts

The following experiments demonstrated that the addition of theanti-inflammatory agent salicylic acid and its derivatives tocombinations of triclosan and silver compounds improved antimicrobialactivity.

LVAD drive lines made of Dacron were impregnated with triclosan, silversulfadiazine and chlorhexidine, with or without salicylic acid, asfollows. One set of pieces of Dacron were uniformly spread with atreatment solution prepared by mixing 30% v/v reagent alcohol(containing triclosan (TC), silver sulfadiazine (AgSD), andchlorhexidine (CHX)) and 70% v/v THF (containing 93A and 60Dpolyurethanes), having final concentrations of 0.1% w/v triclosan, 0.2%w/v silver sulfadiazine, 0.5% w/v chlorhexidine, 4% w/v 93Apolyurethane, and 1% w/v 60D polyurethane. Another set of Dacron pieceswere uniformly spread with a second treatment solution having the samecomponents, but also having a final concentration of 0.5% w/v salicylicacid (the salicylic acid being initially dissolved in the reagentalcohol component). As a control, one set of Dacron pieces was treatedwith a third treatment solution containing salicylic acid and polymerbut lacking triclosan, silver sulfadiazine, and chlorhexidine. TheDacron pieces were dried for 24 hours prior to antimicrobial testing.

In an analogous set of experiments, polyurethane catheters wereimpregnated with triclosan and silver carbonate, with or withoutsalicylic acid or one of its derivatives. One set of polyurethanecatheter segments were therefor dipped in a treatment solution preparedby mixing 20% v/v reagent alcohol/10% v/v ammonia (containing triclosanand silver carbonate ) and 70% v/v THF (containing 93A and 60Dpolyurethanes), having final concentrations of 6% w/v triclosan, 0.4%w/v silver carbonate, 3% w/v 93A polyurethane and 1% w/v 60Dpolyurethane. Three other sets of catheter segments were treated withthe same solution further having a final concentration of 0.5% w/vsalicylic acid, 0.5% w/v acetylsalicylic acid, or 0.5% w/vparaaminosalicylic acid, respectively (the salicylic acid or derivativethereof being first dissolved in the ethanol/ammonia solution). Ascontrols, another three sets of catheters were impregnated usingtreatment solutions as above, containing either 0.5% w/v salicylic acid,0.5% w/v acetylsalicylic acid, or 0.5% w/v paraaminosalicylic acid andpolymer, but lacking triclosan or silver carbonate. The treatedcatheters were dried for 24 hours prior to antimicrobial testing.

Antimicrobial testing was performed by placing the Dacron drive line orcatheter segment on trypticase soy agar seeded with 5×10⁸ cfu ofPseudomonas aeruginosa. The zones of inhibition were measured afterincubation of the plates at 37° C. for 24 hours. The results, presentedin Table 19, illustrate that both hydrophilic (polyurethane) andhydrophobic (Dacron) medical devices can be rendered infection resistantand that anti-inflammatory agents such as salicylates enhanceantimicrobial activity.

TABLE 19 Zones of Inhibition (mm) against P. aeruginosa Agents in LVADPolyurethane Treatment Solution DriveLine Catheters 0.1% TC + 0.2%AgSD + 0.5% CHX 12 — 0.1% TC + 0.2% AgSD + 0.5% CHX + 15 — 0.5%Salicylic acid 0.5% Salicylic Acid  0 — 6% TC + 0.4% Ag₂CO₃ —  7 6% TC +0.4% Ag₂CO_(3 + 0.5%) — 11 Salicylic Acid 6% TC + 0.4% Ag₂CO₃ + 0.5% —11 Acetylsalicylic Acid 6% TC + 0.4% Ag₂CO₃ + 0.5% — 11Paraaminosalicylic Acid 0.5% Salicyic Acid —  0 0.5% AcetylsalicylicAcid —  0 0.5% Paraaminosalicylic Acid —  0

18.0 EXAMPLE Anti-microbial efficacy of Combinations of Silver Salts andChlorinated Phenolic Compounds

Silver compounds, in particular silver salts and various phenoliccompounds were combined to study prolonged anti-microbial efficacy ofthe various compositions. Catheter segments for study were prepared bytreating a polyurethane catheter segment in a treatment solution having70% v/v THF and 30% v/v reagent alcohol and concentrations of 3% w/v 93Apolyurethane and 1% w/v 60D polyurethane, having final concentrations ofagents set forth in Table 20. Then segments were placed on petri dishesseeded with Pseudomonas aeruginosa. Table 3 illustrates the zones ofinhibition of Pseudomonas aeruginosa over a three day period of Ag₂CO₃and Ag₂CO₃ in combination with three phenolic compositions, (1)parachlorometaxylenol (PCMX), (2) o-phenyl phenol and (3) p-tertiaryamyl phenol, and compared their respective efficacy to triclosan andAg₂CO₃. As shown in Table 20 it appears that a synergistic effect occurswhen chlorinated phenols are combined with silver salt exhibitingprolonged anti-microbial activity.

TABLE 20 Zones of Inhibiton (mm) DAY Drugs in Catheter 1 2 3 6%triclosan + 0.6% Ag₂CO₃ 11 10 6 6% PCMX + 0.6% Ag₂CO₃ 12 10 7 6%0-phenyl phenol + 0.6% Ag₂CO₃ 10  0 0 6% p-tertiary amyl phenol + 0.6%Ag₂CO₃ 10  0 0 0.6% Ag₂CO₃ 10  0 0

19.0 Antimicrobial Efficacy of Hydrophilic or Hydrophobic Matrix Systemsby Addition of Hydrogel Polymer

We tested the effect on antimicrobial activity of adding a hydrogelpolymer such as polyvinyl pyrrolidone (PVP) to treatment solutionscontaining triclosan, silver compound, and polyurethanes, and then usingsuch solutions to treat medical devices. Polyurethane catheter segmentswere dipped in one of the following two treatment solutions:

(i) a treatment solution prepared by mixing 30% v/v reagent alcohol(containing triclosan and silver carbonate) with 70% v/v THF (containing93A and 60D polyurethanes), having final concentrations of 6% w/vtriclosan, 0.4% w/v silver carbonate, 3% w/v 93A polyurethane, and 1%w/v 60D polyurethane; or

(ii) a treatment solution prepared by mixing 30% v/v reagent alcohol(containing triclosan and silver carbonate) with 70% v/v THF (containing60D polyurethane and PVP), having final concentrations of 6% w/vtriclosan, 0.4% w/v silver carbonate, 3% w/v 60D polyurethane, and 2%w/v PVP.

The treated catheter segments were then dried for 24 hours and thentested for antimicrobial activity by measuring the zones of inhibitionThe antimicrobial properties of the material were then tested bymeasuring the zones of inhibition produced against S. epidermidis and P.aeruginosa after placing the treated material on a trypticase soy agarplate seeded with 0.3 ml of 10⁸ cfu/ml bacterial culture and incubatingat 37° C. for 24 hours. In addition, the amount of triclosan present percentimeter of catheter was determined spectrophotometrically. Theresults are shown in Table 21.

TABLE 21 Zones of Inhibition (mm) Compounds in vs. vs. TreatmentSolution μg TC/cm S. epidermidis P. aeruginosa 6% TC + 0.4% Ag₂CO₃ + 42511 6.5 3% 93A PU + 1% 60D PU 6% TC + 0.4% Ag₂CO₃ + 397 18 10 3% 60D PU +2% PVP

In other experiments, the effect of PVP incorporated into a hydrophobicarticle, i.e., Dacron material for LVAD drive lines, was determined. Inparticular, pieces of Dacron were uniformly spread with one of the twofollowing treatment solutions:

(iii) a treatment solution prepared by mixing 10% v/v reagent alcohol(containing triclosan, chlorhexidine diacetate (CHA), chlorhexidine freebase (CHX) and silver sulfadiazine) with 90% v/v THF (containing 93A and60D polyurethanes), having final concentrations of 0.2% w/v triclosan,0.3% w/v chlorhexidine diacetate, 0.2% w/v chlorhexidine free base, 0.2%w/v silver sulfadiazine, 4% w/v 93A polyurethane, and 1% w/v 60Dpolyurethane, or

(iv) a treatment solution prepared by mixing 10% v/v reagent alcohol(containing triclosan, chlorhexidine diacetate (CHA), chlorhexidine freebase (CHX) and silver sulfadiazine) with 90% v/v THF (containing 93A and60D polyurethanes and PVP and polyvinylchloride (“PVC”)), having finalconcentrations of 0.2% w/v triclosan, 0.3% w/v chlorhexidine diacetate,0.2% w/v chlorhexidine free base, 0.2% w/v silver sulfadiazine, 4% w/v93A polyurethane, 1% w/v 60D polyurethane, 2% w/v PVP and 4% w/v PVC.

The treated Dacron was allowed to dry for 24 hours and then attached tothe outer surface of silicon tubing using a silicon adhesive to producea drive line. The resulting drive lines were then tested forantimicrobial activity by measuring the zones of inhibition producedagainst S. epidermidis, P. aeruginosa, and C. albicans after placing thetreated material on a trypticase soy agar plate seeded with 0.3 ml of10⁸ cfu/ml bacterial or yeast culture and incubating at 37° C. for 24hours. In addition, the amounts of triclosan and chlorhexidine presentper centimeter of Dacron were determined spectrophotometrically. Theresults are shown in Table 22.

TABLE 22 Zones of Inhibition (mm) Group μg TC/cm μg CHX/cm v. S.epidermidis v. P. aeruginosa v. C. albicans LXI 387 662 17 11.5 14 LXII420 480 22 15 16

As illustrated in Tables 21 and 22, the use of a hydrogel such as PVP ina hydrophilic (e.g., polyurethane) or hydrophobic (e.g., PVC) matrixallows better drug release as evidenced by greater zones of inhibition.

Various publications are cited herein, which are hereby incorporated byreference in their entireties.

1. An anti-infective medical article prepared by exposing apolymer-containing medical article, for an effective period of time, toa treatment solution comprising between about 0.1 and 5 percent of ametal compound, between about 0.1 and 20 percent triclosan, and betweenabout 0.5 and 10 percent of a hydrogel, wherein neither the treatmentsolution nor the medical article contain chlorhexidine or achlorhexidine salt.
 2. The anti-infective medical article of claim 1,where the metal compound is a silver compound.
 3. The anti-infectivemedical article of claim 1, where the hydrogel comprises polyvinylpyrrolidone.
 4. An anti-infective medical article prepared by exposing apolymer-containing medical article, for an effective period of time, toa treatment solution comprising between about 0.1 and 5 percent of asilver compound, between about t0.1 and 20 percent of triclosan, andbetween about 1 and 5 percent of an anti-inflammatory agent, whereinneither the treatment solution nor the medical article containchlorhexidine or a chlorhexidine salt.
 5. The anti-infective medicalarticle of claim 4, where the anti-inflammatory agent is salicylic acidor a derivative thereof.
 6. The anti-infective medical article of claim4, where the treatment solution further comprises an additionalantimicrobial agent.
 7. The anti-infective medical article of claim 6,where the additional antimicrobial agent is selected from the groupconsisting of gramicidin, polymixin, norfloxacin, sulfamylon,polyhexamethylene biguanide, alexidine, minocycline, iodine benzalkoniumchloride and rifampicin.
 8. The anti-infective medical article of claim4 which is a polytetrafluoroethylene graft.